FGF19, FGF21, and FGF23 form a unique subfamily of fibroblast growth factors (FGFs). Unlike other FGFs, all three have been shown to function as endocrine hormones in the regulation of various metabolic processes (Fukumoto, (2008). Endocr. J. 55:23-31). For example, FGF23 originates in bone and regulates phosphate homeostasis in kidney (Fukumoto & Yamashita, (2007) Bone 40:1190-1195), FGF21 is expressed predominantly in liver but can signal in adipose tissue (Ogawa et al., (2007) Proc. Natl. Acad. Sci. U.S.A. 104:7432-7437), and FGF19 is secreted from ileum and functions as an enterohepatic signal for the regulation of bile acid metabolism (Inagaki et al. (2005) Cell. Metab. 2:217-225).
FGF19 and FGF21 appear to share many similarities with reported effects on the regulation of glucose, lipid, and energy metabolism. Both FGF19 and FGF21 transgenic mice are resistant to diet induced obesity, have lower body fat mass, and improved insulin sensitivity, glucose disposal, and plasma lipid parameters (Tomlinson et al., (2002) Endocrinology 143:1741-1747; Fu et al., (2004) Endocrinology 145:2594-2603; Kharitonenkov et al. (2005) J Clin Invest 115:1627-1635; Xu et al., (2008) Diabetes 58:250-59). Injection of recombinant FGF19 or FGF21 proteins in diabetic mouse models resulted in the reduction of serum glucose and insulin levels, improvements in glucose tolerance and liver steatosis, and reduction in body weight (Kharitonenkov et al., (2005) J. Clin. Invest. 115:1627-1635; Xu et al. (2008) Diabetes 58:250-59). In addition, FGF21 has also been shown to improve glucose, insulin and lipid profiles with reduced body weight in diabetic rhesus monkeys (Kharitonenkov et al., (2007) Endocrinology 148:774-781). Taken together, these observations signify the potential utility of these molecules as novel therapies for the treatment of diabetes and obesity.
Although this subfamily displays unique features as compared to other FGF molecules (Kurosu & Kuro-o, (2008) Curr. Opin. Nephrol. Hypertens. 17:368-372 (2008); Wu et al., (2008) J. Biol. Chem. 283(48):33304-9), FGF19, hepatocellular carcinoma (HCC) formation was observed in transgenic mice overexpressing FGF19 in skeletal muscle (Nicholes et al., (2002) Am. J. Pathol. 160:2295-2307). This has been a consideration in developing FGF19 as a therapy for diabetes, obesity and other metabolic disorders.
A chimeric polypeptide that exhibits potential for therapeutic use, while at the same time does not exhibit undesirable properties, such as mitogenicity, that would compromise the use of the polypeptide as a therapeutic, is therefore desirable.